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ID PMID Title PublicationDate abstract
19144572 Antibody titers predict clinical features of autoimmune autonomic ganglionopathy. 2009 Mar 12 Autoimmune autonomic ganglionopathy is a disorder of isolated autonomic failure associated with antibodies to the nicotinic acetylcholine receptor of the autonomic ganglia resulting in severe orthostatic intolerance, syncope, constipation, gastroparesis, urinary retention, dry mouth, dry eyes, blurred vision and anhidrosis. We report the autonomic test results, antibody titers and clinical findings in 8 patients with antibodies to the nicotinic acetylcholine receptor of the autonomic ganglia. There was a sigmoidal relation between the antibody titers and the fall in systolic blood pressure (r(2)=0.84). The threshold occurred with antibody titers of approximately 1 nmol/l. Over the linear portion of the sigmoid curve, with antibody titers in the 1-3 nmol/l range, increasing antibody titers resulted in more severe orthostatic hypotension (r=0.94, P<0.001). The saturation point of the sigmoidal relation occurred at approximately 3 nmol/l with drops in systolic blood pressure of approximately 100 mmHg during upright tilt. The antibody titers correlated inversely with the Valsalva ratio (r=-0.87, P<0.001), the 30:15 ratio (r=-0.84, P<0.001) and the expiratory to inspiratory ratio (r=-0.67, P<0.01). Patients with orthostatic intolerance, anhidrosis, constipation, urinary dysfunction, sicca syndrome and pupillary dysfunction had higher antibody titers than subjects that did not (P<0.01 in all cases). Autoimmune autonomic ganglionopathy is a clinically heterogeneous disease with variable presentation, particularly in subjects with lower antibody titers. Our data suggest that patients with higher antibody titers have wide spread dysautonomia while those with lower antibody levels may present with, or evolve into, more focal or restricted presentations.
20651091 Sphingosine-1-phosphate signaling in human submandibular cells. 2010 Oct Sphingosine-1-phosphate (S1P) is a significant lipid messenger modulating many physiological responses. S1P plays a critical role in autoimmune disease and is suggested to be involved in Sjögren's syndrome pathology. However, the mechanism of S1P signaling in salivary glands is unclear. Here we studied the effects of S1P on normal human submandibular gland cells. S1P increased levels of the intracellular Ca(2+) concentration ([Ca(2+)](i)), which was inhibited by pre-treatment with U73122 or 2-aminoethoxydiphenyl borate (2-APB). Pre-treated S1P did not inhibit subsequent carbachol-induced [Ca(2+)](i) increase, which suggests that S1P and muscarinic signaling are independent of each other. S1P1, S1P2, and S1P3 receptors SphK1 and SphK2 were commonly expressed in human salivary gland cells. S1P, but not carbachol, induces the expression of interleukin-6 and Fas. Our results suggest that S1P triggers Ca(2+) signaling and the apoptotic pathway in normal submandibular gland cells, which suggests in turn that S1P affects the progression of Sjögren's syndrome.
19141059 Systemic treatment of anti-CD4CD25 T cell monoclonal antibody exacerbates sialoadenitis in 2009 Feb BACKGROUND: The maintenance mechanisms of peripheral tolerance by CD4(+)CD25(+) T cells before the development of sialoadenitis in secondary Sjögren's syndrome (sSS) are not well understood. The aim of the present study is to examine the effect of reduction of CD4(+)CD25(+) T cells on the development of sialoadenitis during the early life in female NZB x NZWF(1) (B/WF(1)) mice, a model for human sSS. METHODS: Female B/WF(1) mice at 3 days after birth were treated with either anti-mouse CD4(+)CD25(+) T cells rat IgG(1) monoclonal antibody (mAb) or Rat IgG(1)(control). At 25 weeks of age, autoantibodies against nucleus and cytoplasm of ductal epithelial and myoepithelial cells, and histpathology of submandibular glands were examined in the mAb-treated and control groups. Also the development of anti-Ro/SS-A antibodies was examined until 25 weeks of age in both groups. RESULTS: The mAb-treated group showed severe lesions with the development of autoantibodies compared to the control group. CONCLUSIONS: The present results suggest that peripheral CD4(+)CD25(+) T cells may, at least in part, contribute to down-regulate the development of sialoadenitis in submandibular glands of lupus-prone female B/WF(1) mice during their early life.
19281499 Demographic characteristics of patients with severe neuropathic pain secondary to failed b 2009 May BACKGROUND: Neuropathic pain commonly affects the back and legs and is associated with severe disability and psychological illness. It is unclear how patients with predominantly neuropathic pain due to failed back surgery syndrome (FBSS) compare with patients with other chronic pain conditions. AIMS: To present data on characteristics associated with FBSS patients compared with those with complex regional pain syndrome, rheumatoid and osteoarthritis, and fibromyalgia. METHODS: The PROCESS (Prospective Randomized Controlled Multicenter Trial of the Effectiveness of Spinal Cord Stimulation, ISRCTN 77527324) trial randomized 100 patients to spinal cord stimulation (n = 52) plus conventional medical management (CMM) or CMM alone (n = 48). Baseline patient parameters included age, sex, time since last surgery, employment status, pain location and severity (visual analogue scale), health-related quality of life (HRQoL), level of disability, medication, and nondrug therapies. Reference population data was drawn from the literature. RESULTS: At baseline, patients in the PROCESS study had a similar age and gender profile compared with other conditions. PROCESS patients suffered from greater leg pain and had lower HRQoL. PROCESS patients treatment cost was higher and they commonly took opioids, while antidepressants and nonsteroidal anti-inflammatory drugs were more often used for other conditions. Prior to baseline, 87% of patients had tried at least 4 different treatment modalities. CONCLUSIONS: Patients suffering from chronic pain of neuropathic origin following FBSS often fail to obtain adequate relief with conventional therapies (eg, medication, nondrug therapies) and suffer greater pain and lower HRQoL compared with patients with other chronic pain conditions. Neuropathic FBSS patients may require alternative and possibly more (cost-) effective treatments, which should be considered earlier in their therapeutic management.
20087719 [Surgical principles and clinical experiences with the DUROM hip resurfacing system using 2009 Dec OBJECTIVE: Objective Bone-preserving hip resurfacing in young and active patients using a soft-tissue-sparing, modified transgluteal, lateral approach. INDICATIONS: Primary hip osteoarthritis in physically active, working patients aged < 65 years (males) and < 60 years (females). Good bone quality. CONTRAINDICATIONS: Male patients > or = 65 years of age, female patients > or = 60 years of age. Necrosis of the femoral head. Varus deformity of the femoral neck with a reduced horizontal femoral offset. Femoral head cysts (> 1 cm in diameter). Infection. Osteoporosis. Rheumatoid arthritis. Tumor. Reduced renal function. Leg length difference (> or = 1 cm). Metal allergy. Previous femoral neck fracture. Previous intertrochanteric femoral osteotomies. SURGICAL TECHNIQUE: Supine position of the patient. Modified transgluteal, lateral approach to the hip joint. Luxation of the femoral head. First, reaming of the femoral head to improve visualization of the acetabular cup. Central positioning of the guide wire in the femoral neck in a slight valgus position of approximately +5 degrees to the anatomic collodiaphyseal (CCD) angle using the mechanical targeting device. Overdrilling of the central guide wire to the appropriate depth for the implant. Central insertion of the guide rod. Preparation of the femoral head over the guide rod using cylinder cutters one or two sizes larger than the smallest possible femoral component. Cement-free implantation of the acetabular component according to the predetermined definitive size of the femoral component. Final preparation of the femoral head using profile, surface and forming cutter. Following cemented implantation of the femoral component, repositioning of the hip joint and conclusion of the surgical procedure. POSTOPERATIVE MANAGEMENT: Mobilization of the patient using two forearm crutches as of the 1st day after surgery. Removal of the Redon drains after 24 h. Partial weight bearing of 20 kg for 3 weeks under continuation of thrombosis prophylaxis. Limitation of hip flexion to 90 degrees during the first 6 postoperative weeks, and no adduction and forced external rotation allowed in order to avoid luxation. Avoidance of sports involving the loads of jumping and axial impact loading for 12 postoperative months. RESULTS: Analysis involved the pre- and postoperative functions of 72 patients with a total of 82 prostheses and a mean durability time of 29.2 +/- 11 months based on the Harris Hip Score (HHS), the modified UCLA (University of California, Los Angeles) activity index, and the Merle d'Aubigné Score. Postoperatively, prosthetic angle and femoral offset as well as periprosthetic signs of loosening/lytic areas were assessed by means of radiology and compared with the preoperative CCD angle and femoral offset. Compared to the preoperative evaluation, follow-up yielded a significant increase in the average HHS values (94 +/- 4.6 vs. 40.1 +/- 7 points), the modified UCLA activity index (8.9 +/- 2.6 vs. 4.6 +/- 2.2), and the Merle d'Aubigné Score (17.9 +/- 1.9 vs. 7.3 +/- 2.4; p < or = 0.05). In 98.8%, a solid osteointegration of the cup and femoral components was observed. The average deviation of the physiological CCD angle (136.6 degrees +/- 3.6 degrees ) from the postoperative angle of the prosthesis (142.6 degrees +/- 4.9 degrees ) was 6 degrees +/- 2.8 degrees . The postoperative femoral offset was reduced by an average of 2.3 mm compared to the preoperative offset. During clinical follow-up n = 2 prostheses (2.5%) required revision (one femoral neck fracture; one periarticular ossification [Brooker III]).
19895991 Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signali 2009 Nov BACKGROUND: TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. OBJECTIVE: To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment. METHODS: In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time. RESULTS: In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels. CONCLUSION: Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response.
19602530 Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combin 2009 Jul 14 OBJECTIVES: To investigate the cost effectiveness of cyclo-oxygenase-2 (COX 2) selective inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs), and the addition of proton pump inhibitors to these treatments, for people with osteoarthritis. DESIGN: An economic evaluation using a Markov model and data from a systematic review was conducted. Estimates of cardiovascular and gastrointestinal adverse events were based on data from three large randomised controlled trials, and observational data were used for sensitivity analyses. Efficacy benefits from treatment were estimated from a meta-analysis of trials reporting total Western Ontario and McMaster Universities (WOMAC) osteoarthritis index score. Other model inputs were obtained from the relevant literature. The model was run for a hypothetical population of people with osteoarthritis. Subgroup analyses were conducted for people at high risk of gastrointestinal or cardiovascular adverse events. Comparators Licensed COX 2 selective inhibitors (celecoxib and etoricoxib) and traditional NSAIDs (diclofenac, ibuprofen, and naproxen) for which suitable data were available were compared. Paracetamol was also included, as was the possibility of adding a proton pump inhibitor (omeprazole) to each treatment. MAIN OUTCOME MEASURES: The main outcome measure was cost effectiveness, which was based on quality adjusted life years gained. Quality adjusted life year scores were calculated from pooled estimates of efficacy and major adverse events (that is, dyspepsia; symptomatic ulcer; complicated gastrointestinal perforation, ulcer, or bleed; myocardial infarction; stroke; and heart failure). RESULTS: Addition of a proton pump inhibitor to both COX 2 selective inhibitors and traditional NSAIDs was highly cost effective for all patient groups considered (incremental cost effectiveness ratio less than pound1000 (euro1175, $1650)). This finding was robust across a wide range of effectiveness estimates if the cheapest proton pump inhibitor was used. In our base case analysis, adding a proton pump inhibitor to a COX 2 selective inhibitor (used at the lowest licensed dose) was a cost effective option, even for patients at low risk of gastrointestinal adverse events (incremental cost effectiveness ratio approximately pound10 000). Uncertainties around relative adverse event rates meant relative cost effectiveness for individual COX 2 selective inhibitors and traditional NSAIDs was difficult to determine. CONCLUSIONS: Prescribing a proton pump inhibitor for people with osteoarthritis who are taking a traditional NSAID or COX 2 selective inhibitor is cost effective. The cost effectiveness analysis was sensitive to adverse event data and the specific choice of COX 2 selective inhibitor or NSAID agent should, therefore, take into account individual cardiovascular and gastrointestinal risks.
21274875 Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct 2011 Feb Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Despite limited benefits, ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for cholestatic disorders. Retinoic acid (RA) is a ligand for nuclear receptors that modulate bile salt homeostasis. RA also possesses immunomodulatory effects and is used to treat acute promyelocytic leukemia and inflammatory disorders such as psoriasis, acne, and rheumatoid arthritis. To test whether the supplementation of RA with UDCA is superior to UDCA alone for treating cholestasis, male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 days and were treated with phosphate-buffered saline (PBS), UDCA, all-trans retinoic acid (atRA), or UDCA and atRA by gavage. Treatment with UDCA and atRA substantially improved animal growth rates, significantly reduced liver fibrosis and bile duct proliferation, and nearly eliminated liver necrosis after BDL. Reductions in the bile salt pool size and liver hydroxyproline content were also seen with treatment with atRA or atRA and UDCA versus PBS and UDCA. Furthermore, atRA and UDCA significantly reduced liver messenger RNA and/or protein expression of transforming growth factor β1 (Tgf-β1), collagen 1a1 (Col1A1), matrix metalloproteinase 2 (Mmp2), cytokeratin 19, α-smooth muscle actin (α-SMA), cytochrome P450 7A1 (Cyp7a1), tumor necrosis factor α, and interleukin-β1. The molecular mechanisms of this treatment were also assessed in human hepatocytes, hepatic stellate cells, and LX-2 cells. atRA alone or in combination with UDCA greatly repressed CYP7A1 expression in human hepatocytes and significantly inhibited COL1A1, MMP2, and α-SMA expression and/or activity in primary human hepatic stellate cells and LX-2 cells. Furthermore, atRA reduced TGF-β1-induced Smad2 phosphorylation in LX-2 cells. CONCLUSION: Our findings indicate that the addition of RA to UDCA reduces the bile salt pool size and liver fibrosis and might be an effective supplemental therapy with UDCA for cholestatic diseases.
21094147 Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction. 2010 Dec 17 Abnormal lung inflammation and oxidant burden are associated with a significant reduction in histone deacetylase 2 (HDAC2) abundance and steroid resistance. We hypothesized that Nrf2 regulates steroid sensitivity via HDAC2 in response to inflammation in mouse lung. Furthermore, HDAC2 deficiency leads to steroid resistance in attenuating lung inflammatory response, which may be due to oxidant/antioxidant imbalance. Loss of antioxidant transcription factor Nrf2 resulted in decreased HDAC2 level in lung, and increased inflammatory lung response which was not reversed by steroid. Thus, steroid resistance or inability of steroids to control lung inflammatory response is dependent on Nrf2-HDAC2 axis. These findings have implications in steroid resistance, particularly during the conditions of oxidative stress when the lungs are more susceptible to inflammatory response, which is seen in patients with chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, and inflammatory bowel disease.
19950292 Rituximab may form a complex with IgMkappa mixed cryoglobulin and induce severe systemic r 2009 Dec OBJECTIVE: To report on 6 cases of hepatitis C virus (HCV)-induced mixed cryoglobulinemia (MC) vasculitis in patients who developed severe systemic reactions after rituximab infusion, and to report the results of the in vitro analysis of the underlying immunologic mechanisms. METHODS: Twenty-two HCV-infected patients with MC vasculitis received rituximab infusions (a low-dose protocol cycle with 375 mg/m2/week for 4 consecutive weeks in 18 patients and a high-dose protocol cycle with 1,000 mg on days 1 and 15 in 4 patients). Systemic drug reactions following rituximab infusion were recorded and analyzed clinically and immunochemically. RESULTS: Six of 22 patients (27.3%) experienced systemic drug reactions after rituximab infusion. Four patients developed a severe flare of MC vasculitis 1 or 2 days after rituximab infusion. Two patients developed serum sickness syndrome 7 and 9 days after the first 1,000 mg rituximab infusion. Compared with patients without drug reactions, those with drug reactions had higher mixed cryoglobulin levels (mean+/-SD 1.4+/-0.82 gm/liter versus 0.71+/-0.77 gm/liter; P=0.0475) and lower C4 levels (mean+/-SD 0.02+/-0.006 gm/liter versus 0.07+/-0.07 gm/liter; P=0.02), and more of them received 1,000 mg high-dose rituximab protocol (50% versus 6.25%; P=0.046). In vitro immunochemical assays showed that rituximab formed a complex with the cryoprecipitating IgMkappa that had rheumatoid factor (RF) activity. Moreover, the in vitro addition of rituximab to serum containing an RF-positive IgMkappa type II mixed cryoglobulin was associated with visibly accelerated cryoprecipitation. CONCLUSION: In HCV-associated MC vasculitis, rituximab may form a complex with RF-positive IgMkappa, leading to accelerated cryoprecipitation and to severe systemic reactions. Rituximab should be administered with caution in MC vasculitis, with use of the 375 mg protocol and plasma exchanges prior to rituximab infusion in patients with high baseline levels of mixed cryoglobulin.
20146265 Heat-solubilized curry spice curcumin inhibits antibody-antigen interaction in in vitro st 2010 Aug Chronic and complex autoimmune diseases, currently treated palliatively with immunosuppressives, require multi-targeted therapy for greater effectiveness. The naturally occurring polyphenol curcumin has emerged as a powerful "nutraceutical" that interacts with multiple targets to regress diseases safely and inexpensively. Up to 8 g/day of curcumin for 18 months was non-toxic to humans. However, curcumin's utility is limited by its aqueous insolubility. We have demonstrated a heat-mediated 12-fold increase in curcumin's aqueous solubility. Here, we show by SDS-PAGE and surface plasmon resonance that heat-solubilized curcumin binds to proteins. Based on this binding we hypothesized that heat-solubilized curcumin or turmeric would prevent autoantibody targeting of cognate autoantigens. Heat-solubilized curcumin/turmeric significantly decreased binding of autoantibodies from Sjögren's syndrome (up to 43/70%, respectively) and systemic lupus erythematosus (up to 52/70%, respectively) patients as well as an animal model of Sjögren's syndrome (up to 50/60%, respectively) to their cognate antigens. However, inhibition was not specific to autoimmunity. Heat-solubilized curcumin/turmeric also inhibited binding of commercial polyclonal anti-spectrin to spectrin (50/56%, respectively). Thus, we suggest that the multifaceted heat-solubilized curcumin can ameliorate autoimmune disorders. In addition, the non-toxic curcumin could serve as a new protein stain in SDS-PAGE even though it is less sensitive than the Coomassie system which involves toxic chemicals.
19946023 The immunoregulatory role of vitamins A, D and E in patients with primary Sjogren's syndro 2010 Feb OBJECTIVE: The aim of the present study was to investigate the immunomodulating role of fat-soluble vitamins in 25 patients with primary SS (pSS) and 15 healthy individuals. METHODS: Plasma levels of vitamins A, D and E were determined by HPLC. Peripheral NK, NK T cells, T-cell subsets, B cells, IL-10 producing Tr1 cells, CD4(+)CD25(+) Treg cells and Th17 were determined by flow cytometry. Various Th1- and Th2-soluble cytokines were assessed by ELISA, whereas intracytoplasmic cytokines (IFN-gamma, IL-4, -10 and -17) were measured by flow cytometry. Correlation was assessed between vitamin levels and immunological and clinical parameters. RESULTS: Vitamin A levels did not differ between patients and controls, yet in patients with extraglandular manifestations (EGMs) a significant decrease in vitamin A levels was apparent compared with pSS patients without EGMs (P = 0.005). Vitamin E levels were increased in patients compared with controls (P = 0.004), whereas vitamin D levels were similar in pSS and control subjects. In patients, vitamin A showed a positive correlation with both NK cell (P = 0.038) and Th17 cell (P = 0.025), and a negative correlation with Schirmer's test values (P = 0.035). Positive correlation was found between vitamin E and NK cells (P = 0.043), Th1 cells (P = 0.049) and the Th1/Th2 ratio (P = 0.043). In the control group, we found correlation between vitamin E and serum IL-10 levels (P = 0.003). CONCLUSIONS: Our data suggest that fat-soluble vitamins may be important in immunoregulatory processes in patients with pSS.
19229767 Anti-Ro/SSA autoantibody-mediated regulation of extracellular matrix fibulins in human epi 2009 May OBJECTIVES: The fibulins are a family of extracellular matrix (ECM) molecules that regulate the organ shape along with other growth factors and stromal cells and have recently been shown to be involved in a variety of cellular functions including proliferation, migration, differentiation, and survival. Important changes in acinar and ductal morphology and function, together with pronounced ECM remodelling, are detectable in the labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS). Here we report the in vitro expression of the recently identified ECM proteins fibulin-6 and fibulin-7 by human salivary gland epithelial cells (SGECs). The ability of anti-Ro/SSA autoantibodies (Abs) to modulate fibulin-6 and fibulin-7 expression was investigated. METHODS: Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR were used to analyse fibulin-6 and fibulin-7 mRNA expression. Confocal microscopy and fluorescence-activated cell sorting (FACS) were used to study expression of the proteins in primary human SGEC cultures, established from biopsies of minor LSGs, in both untreated control cells and anti-Ro/SSA Abs-treated cells. RESULTS: The methods used show the expression of fibulin-6 and fibulin-7 in SGECs. Treatment of cells with anti-Ro/SSA Abs results in a down-regulation of fibulin-6 mRNA expression whereas no significant differences were observed in fibulin-7 expression between untreated and treated cells. CONCLUSION: Dysregulation of fibulin expression in SGECs by anti-Ro/SSA Abs may contribute to disorganization of the ECM environment and thus cause injury to the salivary gland architecture and functionality observed in SS.
20731676 New epitopes and function of anti-M3 muscarinic acetylcholine receptor antibodies in patie 2010 Oct M3 muscarinic acetylcholine receptor (M3R) plays a crucial role in the secretion of saliva from salivary glands. It is reported that some patients with Sjögren's syndrome (SS) carried inhibitory autoantibodies against M3R. The purpose of this study is to clarify the epitopes and function of anti-M3R antibodies in SS. We synthesized peptides encoding the extracellular domains of human-M3R including the N-terminal region and the first, second and third extracellular loops. Antibodies against these regions were examined by enzyme-linked immunosorbent assay in sera from 42 SS and 42 healthy controls. For functional analysis, human salivary gland (HSG) cells were preincubated with immunoglobulin G (IgG) separated from sera of anti-M3R antibody-positive SS, -negative SS and controls for 12 h. After loading with Fluo-3, HSG cells were stimulated with cevimeline hydrochloride, and intracellular Ca(2+) concentrations [(Ca(2+) )i] were measured. Antibodies to the N-terminal, first, second and third loops were detected in 42·9% (18 of 42), 47·6% (20 of 42), 54·8% (23 of 42) and 45·2% (19 of 42) of SS, while in 4·8% (two of 42), 7·1% (three of 42), 2·4% (one of 42) and 2·4% (one of 42) of controls, respectively. Antibodies to the second loop positive SS-IgG inhibited the increase of (Ca(2+) )i induced by cevimeline hydrochloride. Antibodies to the N-terminal positive SS-IgG and antibodies to the first loop positive SS-IgG enhanced it, while antibodies to the third loop positive SS-IgG showed no effect on (Ca(2+) )i as well as anti-M3R antibody-negative SS-IgG. Our results indicated the presence of several B cell epitopes on M3R in SS. The influence of anti-M3R antibodies on salivary secretion might differ based on these epitopes.
20643530 Salivary gland epithelial cells (SGEC): carriers of exquisite B7-2 (CD86) costimulatory mo 2010 Nov Costimulatory molecules are cell-surface glycoproteins that can direct, modulate and fine tune immune responses. B7-2(CD86) costimulatory molecules are considered as major regulators of T cell responses, acting by appropriate interactions with the stimulatory CD28 or inhibitory CTLA-4 receptors found on T cells. Although their expression is thought to be restricted in lymphoid cells, evidence raised during the last decade show their expression in other types of cells, including human non-neoplastic salivary gland epithelial cells (SGEC). The expression of B7-2 molecules by SGECs requires special attention, due to their unique expression pattern and distinctive binding properties. Thus, SGECs express three B7-2 alternate transcripts that encode the full-length protein, the soluble form and a truncated membrane-bound molecule, that lacks the IgV-like counter-receptor binding domain and has a negative regulatory role. A similar pattern of expression is observed in monocytes, but not in several other types of cells, including dendritic cells. Furthermore, the full-length B7-2 molecules in SGEC display unique binding properties, denoted by the functional interaction with CD28 receptor, but reduced binding of the negative regulator CTLA-4. These distinctive features suggest the tight regulation of B7-2 molecules expression and indicate the key immunoregulatory role of SGECs.
20012627 Sudden paraplegia following epidural lipomatosis and thoracal compression fracture after l 2011 Sep Sudden paraplegia secondary to the posterior spinal epidural compression and vertebral compression fracture as a complication in corticosteroid treatment is extremely rare. The authors presented a case 49-year-old man with chronic relapsing attack of Still's disease. After the identification of pathology, the surgical evacuation of lipid tissue and pedicle-based instrumentation showed therapeutic success. To the authors' knowledge, this is the first case showing both vertebral fracture and paraplegia that required urgent surgery in the follow-up Still's disease.
20483768 African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. 2010 Jun 15 The TNF alpha-induced protein 3 (TNFAIP3) is an ubiquitin-modifying enzyme and an essential negative regulator of inflammation. Genome-wide association studies have implicated the TNFAIP3 locus in susceptibility to autoimmune disorders in European cohorts, including rheumatoid arthritis, coronary artery disease, psoriasis, celiac disease, type 1 diabetes, inflammatory bowel disease, and systemic lupus erythematosus (SLE). There are two nonsynonymous coding polymorphisms in the deubiquitinating (DUB) domain of TNFAIP3: F127C, which is in high-linkage disequilibrium with reported SLE-risk variants, and A125V, which has not been previously studied. We conducted a case-control study in African-American SLE patients using these coding variants, along with tagging polymorphisms in TNFAIP3, and identified a novel African-derived risk haplotype that is distinct from previously reported risk variants (odds ratio=1.6, p=0.006). In addition, a rare protective haplotype was defined by A125V (odds ratio=0.31, p=0.027). Although A125V was associated with protection from SLE, surprisingly the same allele was associated with increased risk of inflammatory bowel disease. We tested the functional activity of nonsynonymous coding polymorphisms within TNFAIP3, and found that the A125V coding-change variant alters the DUB activity of the protein. Finally, we used computer modeling to depict how the A125V amino acid change in TNFAIP3 may affect the three-dimensional structure of the DUB domain to a greater extent than F127C. This is the first report of an association between TNFAIP3 polymorphisms and autoimmunity in African-Americans.
20200975 Correlates of trabecular and cortical volumetric bone mineral density of the radius and ti 2010 May Quantitative computed tomography (QCT) can estimate volumetric bone mineral density (vBMD) and distinguish trabecular from cortical bone. Few comprehensive studies have examined correlates of vBMD in older men. This study evaluated the impact of demographic, anthropometric, lifestyle, and medical factors on vBMD in 1172 men aged 69 to 97 years and enrolled in the Osteoporotic Fractures in Men Study (MrOS). Peripheral quantitative computed tomography (pQCT) was used to measure vBMD of the radius and tibia. The multivariable linear regression models explained up to 10% of the variance in trabecular vBMD and up to 9% of the variance in cortical vBMD. Age was not correlated with radial trabecular vBMD. Correlates associated with both cortical and trabecular vBMD were age (-), caffeine intake (-), total calcium intake (+), nontrauma fracture (-), and hypertension (+). Higher body weight was related to greater trabecular vBMD and lower cortical vBMD. Height (-), education (+), diabetes with thiazolidinedione (TZD) use (+), rheumatoid arthritis (+), using arms to stand from a chair (-), and antiandrogen use (-) were associated only with trabecular vBMD. Factors associated only with cortical vBMD included clinic site (-), androgen use (+), grip strength (+), past smoker (-), and time to complete five chair stands (-). Certain correlates of trabecular and cortical vBMD differed among older men. An ascertainment of potential risk factors associated with trabecular and cortical vBMD may lead to better understanding and preventive efforts for osteoporosis in men.
19932542 Phase 1 trial of adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of th 2010 Jan BACKGROUND: Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end-stage kidney disease. Antifibrotic agents, such as tumor necrosis factor alpha antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data. STUDY DESIGN: Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor alpha. SETTING & PARTICIPANTS: 10 patients (4 male and 6 female) aged 16.8 +/- 9.0 years with an estimated glomerular filtration rate of 105 +/- 50 mL/min/1.73 m(2) were studied. INTERVENTION: Adalimumab, 24 mg/m(2), every 14 days for 16 weeks (total, 9 doses). OUTCOMES: Pharmacokinetic assessment, tolerability, and safety. MEASUREMENTS: Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state. RESULTS: Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P < 0.001) and clearance was increased by 160% (P < 0.01) in patients with resistant FSGS compared with healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria decreased by > or = 50% in 4 of 10 treated patients. LIMITATIONS: Insufficient power to assess the safety or efficacy of adalimumab therapy for patients with resistant FSGS. CONCLUSIONS: Pharmacokinetic assessment showed increased clearance of adalimumab in patients with resistant primary FSGS and validated the need to evaluate the disposition of novel therapies for this disease to define appropriate dosing regimens. The study provides a rationale to evaluate the efficacy of adalimumab as an antifibrotic agent for resistant FSGS in phase 2/3 clinical trials.
20592286 Polymorphic variants of LIGHT (TNF superfamily-14) alter receptor avidity and bioavailabil 2010 Aug 1 The TNF superfamily member homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes (LIGHT) [TNF superfamily (SF)-14], is a key cytokine that activates T cells and dendritic cells and is implicated as a mediator of inflammatory, metabolic, and malignant diseases. LIGHT engages the lymphotoxin-beta receptor (LTbetaR) and HVEM (TNFRSF14), but is competitively limited in activating these receptors by soluble decoy receptor-3 (DcR3; TNFRSF6B). Two variants in the human LIGHT alter the protein at E214K (rs344560) in the receptor-binding domain and S32L (rs2291667) in the cytosolic domain; however, the functional impact of these polymorphisms is unknown. A neutralizing Ab failed to bind the LIGHT-214K variant, indicating this position as a part of the receptor-binding region. Relative to the predominant reference variant S32/E214, the other variants showed altered avidity with LTbetaR and less with HVEM. Heterotrimers of the LIGHT variants decreased binding avidity to DcR3 and minimized the inhibitory effect of DcR3 toward LTbetaR-induced activation of NF-kappaB. In patients with immune-mediated inflammatory diseases, such as rheumatoid arthritis, DcR3 protein levels were significantly elevated. Immunohistochemistry revealed synoviocytes as a significant source of DcR3 production, and DcR3 hyperexpression is controlled by posttranscriptional mechanisms. The increased potential for LTbetaR signaling, coupled with increased bioavailability due to lower DcR3 avidity, provides a mechanism of how polymorphic variants in LIGHT could contribute to the pathogenesis of inflammatory diseases.